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Uploaded byShagufta Farooqui
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Sympathomimetic Drugs

Sympathomimetic drugs mimic the actions of norepinephrine and epinephrine by binding to adrenergic receptors. They can be classified as direct-acting agonists like epinephrine, indirect-acting agonists like amphetamines, or mixed-action agonists like ephedrine. Common uses include pressor agents, cardiac stimulants, bronchodilators, nasal decongestants, CNS stimulants, and anorectics. Examples discussed in more detail include epinephrine, norepinephrine, dopamine, dobutamine, ephedrine, amphetamines, phenylephrine, and pseudophedrine.

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Prepared by- Shagufta Farooqui Department of Pharmacology Nanded Pharmacy, College, Nanded.
“Fight or Flight”
Drugs that partially or completely mimic the actions of norepinephrine (NE) or epinephrine (Epi). Epinephrine: Also known as adrenaline. A substance produced by the medulla inside of the adrenal gland. These are drugs which actions is similar to that of Adranaline or of sympathetic stimulation. Sympathomimetic Drugs Adrenaline Nor-Adrenaline
ADRENERGIC TRANSMISSION Adrenergic (more precisely ‘Noradrenergic’) transmission is restricted to the sympathetic division of the ANS. There are three closely related endogenous catecholamines (CAs). Noradrenaline (NA) It acts as transmitter at postganglionic sympathetic sites (except sweat glands, hair follicles and some vasodilator fibres) and in certain areas of brain. Adrenaline (Adr) It is secreted by adrenal medulla and may have a transmitter role in the brain. Dopamine (DA) It is a major transmitter in basal ganglia, limbic system, CTZ, anterior pituitary, etc. and in a limited manner in the periphery.
1.Synthesis of Norepinephrine : It begins with the amino acid tyrosine, which enters the neuron by active transport, perhaps facilitated by a permease. In the neuronal cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa), which is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase, sometimes termed dopa-decarboxylase. 2.Storage norepinephrine in vesicles: The dopamine is actively transported into storage vesicles, where it is converted to norepi-nephrine (the transmitter) by dopamine 3 hydroxylase, an enzyme within the storage vesicle. In noradrenergic neurons, the end product is norepi-nephrine. In the adrenal medulla, the synthesis is carried one step further by the enzyme phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine.
3.Release of Norepinephrine: An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. This release is blocked by drugs such as guanethidine.
4.Action on Post synaptic receptor: Nor epinephrine from the synaptic vesicles the sympathetic system diffuses across the synaptic space and binds to either postsynaptic receptors on the effecte organ or to presynaptic receptors on the nerve ending. Receptors may be divided into alpha (a), beta (B), and dopamine (D) receptors. Drugs that bind to these receptors and modulate or mimic the function of the sympathetic nervous system may be divided into those which augment the system (sympathomimetics) and those which antagonize the system (sympatholytics).
5.Removal of norepinephrine: The nor epinephrine may- (1) diffuse out of the synaptic space and enter the general circulation . (2) be metabolized to O-methylated derivatives by postsynaptic cell membrane-associated catechol O- methyltransferase (COMT) in the synaptic space, or (3) be recaptured by an uptake system that pumps the nor epinephrine back into the neuron.
6.Potential fates of recaptured norepinephrine: Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine.
Classification Direct-acting agonists e.g. epinephrine, norepinephri ne. Indirect- acting agonists amphetamine , Cocaine. Mixed-action agonists Ephedrine, Pseudo ephedrine Adrenergic Drugs
THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS I. Pressor agents Noradrenaline,Phenylephrine,EphedrineMethoxamine, Dopamine Mephentermine II. Cardiac stimulants Adrenaline Dobutamine ,Isoprenaline III. Bronchodilators Isoprenaline Salmeterol, Salbutamol Formoterol,(Albuterol) Bambuterol, Terbutalin
IV. Nasal decongestants Phenylephrine,Naphazoline,XylometazolinePseudoephedrine , Oxymetazoline Phenylpropanolamine V. CNS stimulants Amphetamine Methamphetamine, Dexamphetamine VI. Anorectics Fenfluramine ,Sibutramine ,Dexfenfluramine VII. Uterine relaxant and vasodilators Ritodrine, Salbutamol, Isoxsuprine Terbutaline
Adrenergic Receptors Receptor Location G protein Functions α1 Blood Vessele, Glands, Smooth muscles of iris, Gq Constriction of Blood vessels, Increase secretion α2 CNS Gi CNS Depressent Effect β1 Heart(Myocardium) , Juxtaglomerular apparatus Gs Increase Heart rate, Increase B.P, Increase renal release β2 Lungs, Uterus,GIT Gs Bronchodilation,Rela xation of Uterus,Increase Glycogenolysis β3 Adipose tissues Gs Break down of adipose tissues, Lipolysis
Epinephrine Pharmacological Action Heart: The direct β1 receptor mediated actions of epinephrine are positive chronotropic ( heart rate) and ionotropic ( force of contraction) effect on the heart, increased cardiac output, myocadical contractility, coronary blood flow and so oxygen consumption by heart. The conduction velocity through A-V node, bundle of His, parkinje fibres, atrias and ventricular fibres is increased by epinephrine to cause the above responses. Epi→ B1 receptor → Gs → Ad. cycl. → cAMP → PKA - Ca-channels open →[Ca++ Ca calmodulin complex-MLCK → Phosphorylation of MLC Contraction of myocardial fibre.
Blood Vessels: Both vasoconstriction (α) and vasodilatation (β2) can occur depending on the drug, its dose and vascular bed. Epinephrine mainly acts on small arterioles and precapillary sphincters. It also exerts its action, to some extent, on veins and large arteries. It causes constriction of cutaneous, renal, pulmonary, arterial and venous, and other visceral blood vessels because of the presence of predominant a receptors. It dilates blood vessels of skeletal muscles (at low doses), coronary and liver which is mediated by powerful B2 receptors. At higher dose, it causes vasoconstriction in skeletal muscle.
Blood Pressure: The effect depends on the amine, its dose and rate of administration. At lower concentration slow iv infusion or S.C. injection of epinephrine causes fall in peripheral resistance because vascular Bereceptors are more sensitive than receptors. At High dose or rapid i.v. infusion produces marked increase in systolic as well as diastolic B.P. (as the number of a receptors are more than β2 receptors in blood vessels), which is followed by a fall in the mean B.P. (because when the epinephrine concentration is reduced by degradation, rest of the amount remain attached on more sensitive B2 receptors). This is called as biphasic response of epinephrine on blood pressure.
Smooth Muscle: The GIT of smooth muscle is relaxed by epinephrine. This effect is mediated by both a and B2 receptors on effectors cells and a receptors on the membrane of para sympathetic nerve endings. The α1 receptor activation causes increase in K+ efflux and thereby hyperpolarization of the muscle cell. B2 receptor activation increases cytosolic concentration of CAMP. Stimulation of presynaptic a receptors renders inhibition of release of excitatory neurotransmitter Ach from intramural nerve. These three response combined cause relaxation of GIT smooth muscles.
Sphincter: Epinephrine usually increases sphincter contraction via a receptors (by activation of phospholipase C) Respiratory: Bronchial smooth muscle relaxes (B2 receptors activation - CAMP 1). Uterus: The non-pregnant uterus of human is contracted and pregnant one is relaxed by the drug. It relaxes detrusor muscle (B2 receptors) and contracts the trigone and sphinctor muscles (a receptors) of the bladder.
Metabolism: It stimulates glycogenolysis (P2 mediated) in liver and muscle, causes inhibition of insulin secretion (a mediated) and increases free fatty acids in blood (B1 mediated activation of triglyceride lipase breakdown of triglycerides into free fatty acids and glycerol) Eye: Mydriasis occurs due to contraction of radial muscles (a; receptors) of iris by epinephrine. The intraoccular pressure falls, specially in wide angle glaucoma, due to relaxation of ciliary muscle (B2 receptors).
Skeletal Muscle: It does not directly excite skeletal muscle but facilitates neuromuscular transmission through the activation of a and B2 receptors of somatic Motor neurons releasing Ach rapidly. The twitch tension of white muscle (fast contracting fibres) is increased. Whereas that of red muscle (slow fibres) is reduced. Other B2 agonists (e.g. salbutamol) may also act similarly.
CNS: Being polar compound, epinephrine cannot enter into the CNS but restlessness, apprehension, headache and tremor may occur due to its secondary to some peripheral effects on CNS, skeletal muscles, and intermediary metabolism
GIT : In isolated preparations of gut, relaxation occurs through activation of both α and β receptors. In intact animals and man peristalsis is reduced and sphincters are constricted, but the effects are brief and of no clinical import.
NOREPINEPHRINE (LEVARTERENOL): It is also found in plants and is used pharmacologically as a sympathomimetic. It is a precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. It is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. Mechanism of action: It acts on both alpha-1 and alpha-2 adrenergic receptors to cause vasoconstriction. It functions as a peripheral vasoconstrictor by acting on alpha-adrenergic receptors. It is also an inotropic stimulator of the heart and dilator of coronary arteries as a result of it's activity at the beta-adrenergic receptors.
Dopamine (DA): It is a dopaminergic (D1 and D2) as well as adrenergic α and β1 (but not β2) agonist. The D1 receptors in renal and mesenteric blood vessels are the most sensitive: i.v. infusion of low dose of DA dilates these vessels (by raising intracellular cAMP). This increases g.f.r. In addition DA exerts natriuretic effect by D1 receptors on proximal tubular cells. Moderately high doses produce a positive inotropic (direct β1 and D1 action + that due to NA release), but little chronotropic effect on heart. Vasoconstriction (α1 action) occurs only when large doses are infused.
At doses normally employed, it raises cardiacoutput and systolic BP with little effect on diastolic BP. It has practically no effect on nonvascular α and β receptors; does not penetrate blood-brain barrier—no CNS effects. Dopamine is used in patients of cardiogenic or septic shock and severe CHF wherein it increases BP and urine outflow. It is administered by i.v. infusion (0.2–1 mg/min) which is regulated by monitoring BP and rate of urine formation.
Dobutamine: A derivative of DA, but not a D1 or D2 receptor agonist. Though it acts on both α and β adrenergic receptors, the only prominent action of clinically employed doses (2–8 μg/kg/ min i.v. infusion) is increased force of cardiac contraction and output, without significant change in heart rate, peripheral resistance and BP. As such, it is considered to be a relatively selective β1 agonist. It is used as an inotropic agent in pump failure accompanying myocardial infarction, cardiac surgery, and for short term management of severe congestive heart failure. It is less arrhythmogenic than Adr.
Ephedrine It is an alkaloid obtained from Ephedra vulgaris. Mainly acts indirectly but has some direct action as well on α and β receptors. Repeated injections produce tachyphylaxis, primarily because the neuronal pool of NA available for displacement is small. It is resistant to MAO, therefore, effective orally. It is about 100 times less potent than Adr, but longer acting (4–6 hours). Ephedrine crosses to brain and causes stimulation, but central: peripheral activity ratio is lower than that of amphetamine. Ephedrine can be used for a variety of purposes, but it lacks selectivity, and efficacy is low. Use is now restricted to that in mild chronic bronchial asthma and for hypotension during spinal anaesthesia; occasionally for postural hypotension; 15–60 mg TDS.
Amphetamines These are synthetic compounds having a pharmacological profile similar to ephedrine; orally active with relatively long duration (4–6 hours). They exert potent CNS stimulant and weaker peripheral cardiovascular actions. Maximal selectivity is exhibited by dextroamphetamine and methamphetamine, which in the usual doses produce few peripheral effects. The central actions of amphetamines are largely mediated by release of NA from adrenergic neurones in the brain.
Phenylephrine It is a selective α1 agonist, has negligible β action. It raises BP by causing vasoconstriction. Because it has little cardiac action, reflex bradycardia is prominent. Topically it is used as a nasal decongestant and in the eye for producing mydriasis when cycloplegia is not required. Phenylephrine tends to reduce intraocular tension by constricting ciliary body blood vessels. It is also a frequent constituent of orally administered nasal decongestant preparations.
NASAL DECONGESTANTS These are α agonists which on topical applicationas dilute solution (0.05–0.1%) produce local vasoconstriction. The imidazoline compounds— naphazoline, xylometazoline and oxymetazoline are relatively selective α2 agonist (like clonidine). They have a longer duration of action (12 hours) than ephedrine. After-congestion is claimed to be less than that with ephedrine or phenylephrine. They may cause initial stinging sensation (specially naphazoline). Regular use of these agents for long periods should be avoided because mucosal ciliary function is impaired: atrophic rhinitis and anosmia can occur due to persistent vasoconstriction. They can be absorbed from the nose and produce systemic effects, mainly CNS depression and rise in BP. These drugs should be used cautiously in hypertensives and in those receiving MAO inhibitors.
Pseudophedrine A stereoisomer of ephedrine; causes vasoconstriction, especially in mucosae and skin, but has fewer CNS and cardiac effect and is a poor bronchodilator (little β2 agonistic activity). It has been used orally as a decongestant of upper respiratory tract, nose and eustachian tubes. Combined with antihistaminics, mucolytics, antitussives and analgesics, it is believed to afford symptomatic relief in common cold, allergic rhinitis, blocked eustachian tubes and upper respiratory tract infections. However, no selective action on these vascular beds has been demonstrated; rise in BP can occur, especially in hypertensives.
THERAPEUTIC USES 1.Vascular uses Hypotensi ve states Along with local anaestheti cs Control of local bleeding Nasal decongesta nt Peripheral vascular diseases
2.Cardiac uses Cardiac arrest Partial or complete A- V block Congestive heart failure (CHF)
3. Bronchial asthma and COPD 4. Allergic disorders 5. Mydriatic 6. Uterine relaxant 7. Insulin hypoglycaemia 8. Nocturnal enuresis inchildren
Central uses Attention deficit hyperkinetic disorder (ADHD): Narcolepsy Epilepsy Obesity
ADVERSE EFFECTS AND CONTRAINDICATIONS Transient restlessness, headache, palpitation, anxiety, tremor and pallor may occur after s.c./ i.m. injection of Adrenaline. Marked rise in BP leading to cerebral haemorrhage, ventricular tachycardia/ fibrillation, angina, myocardial infarction are the hazards of large doses or inadvertent i.v. injection of Adrenaline. Adrenaline is contraindicated in hypertensive, hyperthyroid and angina patients. Adrenaline should not be given during anesthesia with halothane (risk of arrhythmias) and to patients receiving β blockers (marked rise in BP can occur due to unopposed α action).
Sympathomimetic Drugs